Prostaglandins of the F series

ABSTRACT

The present invention provides new compounds, 13,14-dihydro-15-keto-PGFs, and vassopressors containing them, which raise blood pressure without substantial ephemeral depression of blood pressure, trachea or enteron contraction effect inherent in usual PGFs.

This is a continuation of application Ser. No. 07/607,791, filed Oct.31, 1990, abandoned, which in turn is a continuation of application Ser.No. 07/189,100, filed May 2, 1988, abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel prostaglandins of the F seriesand vasopressors containing the same.

Prostaglandins of the F series (hereinafter referred to as PGFs) whichcontain a partial structure as a five-membered ring shown in thefollowing formula: ##STR1## may be roughly divided into PGF₁ α: ##STR2##in which the carbon atom at 5-position (referred to as C-5 hereinafter,such nominating is applied to other carbon) and C-6 are singly bonded,and PGF₂ α: ##STR3## in which C-5 and C-6 are doubly bounded, and PGF₃α: ##STR4## in which C-5 and C-6 are, and C-17 and C-18 are are doublybonded. For example, PGF₂ α which exhibits marked oxytocic effect isclinically used to induce or promote pain at the last stage ofpregnancy. Moreover, it is known to have vasopressor effect, however,the effect of PGF₂ α is accompanied with preceding ephemeralvasorelaxation. Further, the typical PG effects on trachea, bronchus andintestine such as increase of airway resistance due to trachealcontraction and abdominal pain due to intestineal contraction, aresimultaneously accompanied with vasopressor effect, therefore, there areproblems to use the PGFs as vasopressors.

On the other hand, prostaglandin F metaboletes in which the bond betweenC-13 and C-14 is saturated, and C-15 is a carbonyl group, are found toexist in human and animal metabolites. These13,14-dihydro-15-keto-prostaglandin Fs are shown in the formulaefollowing: ##STR5## and are known as the metabolites of thecorresponding PGF₁ α, PGF₂ α, and PGF₃ α in vivo. These13,14-dihydro-15-keto-PGFs scarcely exhibit any physiological activitiesthat PGFs inherently possess, and have been reported as thephysiologically-, and the pharmacologically- inactive metabolites (see,Acta Physiologica Scandinabia, 66, P 506(1988)).

SUMMARY OF THE INVENTION

While evaluating pharmacological activities of the derivatives of theabove metabolites, however, the present inventors have found thatcarboxylic-acid esters of the above metabolites themselves,13,14-dihydro-15-keto-PGF analogues, which are carboxylic acids,corresponding salts, and corresponding esters, bearing substituents onC-3, -16, -17, -19, and/or -20 and 13,14-dihydro-15-keto-PGF analogueswhich bear a methyl group or a hydroxymethyl group instead of a hydroxygroup on C-9 or C-11, show vasopressor activity, which is one of thephermaceutical activities of the PGFs. The vasopressor effect of these13,14-dihydro-15-keto-PGFs may raise blood pressure without ephemeralvasorelexation which is inherent to the PGFs. Further,13,14-dihydro-15-keto-PGFs, which show no or extremely reduced trachealand intestineal contraction effects those the PGFs inherently possessare found to have no typical PG effects on trachea, bronchus andintestine.

BRIEF DESCRIPTION OF DRAWING

FIGS. 1-27 are n.m.r. charts of 13,14-dihydro-15-keto-PGFs of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides 13,14-dihydro-15-keto-PGFs and thecorresponding salts shown in the general formula and vasopressorscontaining the compounds; ##STR6## in the formula C-2, -3 double bondmay or may not be located; X is ##STR7## one of four possibilities shownabove R₁ is a hydrogen atom, an alkyl, phenyl, benzoyl, hydroxyalkyl,alkoxyalkyl, trialkylsilyl and tetrapyranyl group;

R₂ is a hydrogen atom or a lower alkyl group;

R₃ and R₃ ' are a hydroxyl, methyl or hydroxymethyl;

R₄ and R₅ are the same or different, and signify a hydrogen atom, alower alkyl or a halogen atom; and

R₆ is either an alkyl group consisted of 4 to 9 carbons which may or maynot be branched one, contain double bonds or may bear alkokysubstituents or the group shown in the formula following: ##STR8##(wherein Y indicates a single bond with C-16, or an oxygen atom; R₇indicates a hydrogen or halogen atom or a halgenated alkyl); exceptingthe compound wherein R₁, R₂, R₄ and R₅ are simultaneously hydrogenatoms, R₆ is a n-Bu, R₃ and R₃ ' are both hydroxyls and C-2 and C-3 aresingly bonded.

X in the general formula represents the four types of the partialstructure illustrated above.

A compound in which --(X)-- signifies ##STR9## is13,14-dihydro-15-keto-PGF₁ s and a compound wherein --(X)-- signifies##STR10## is 13,14-dihydro-15-keto-PGF₂ s. Accordingly, the compoundswherein --(X)-signifies ##STR11## are 13,14-dihydro-6,15-diketo-PGF₁ s,and 13,14-dihydro-15-keto-5,6-dehydro-PGF₂ s, respectively.

In the present invention, R₁ indicates a hydrogen atom, alkyl, phenyl,benzyl, hydroxyalkyl, alkoxyalkyl, trialkylsilyl, and tetrahydropyranyl.A preferable R₁ in the present invention is an alkyl group, morepreferably, a saturated or an unsaturated alkyl group which may or maynot have a side chain and particularly an alkyl group which may contain1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl and the like.

13,14-Dihydro-15-keto PGFs in this invention may be in a salt form. Thesalts are physiologically acceptable ones, for example, salts withalkali metals such as sodium, potassium and salts with alkaline earthmetals such as calcium, magnesium or physiologically acceptable ammoniumsalts, for example, ammonium salts derived from ammonia, methylamine,dimetylamine, cyclopentylamine, benzylamine, piperidine,monoethanolamine, diethanolamine, monomethylmonoethanolamine,tromethamin, lysine, and tetraalkylammonium salt and the like.

R₂ is a hydrogen or a lower alkyl group, especially methyl.

R₃ and R₃ ' are a hydroxyl, methyl or hydroxymethyl. When they are bothhydroxyls, the compound belongs to the general13,14-dihydro-15-keto-PGFs. In the present invention, the compoundswherein R₃ and/or R₃ ' are/is methyl or hydroxymethyl are alsoconsidered as PGFs.

R₃ may be α-oriented or β-oriented and R'₃ may be α-oriented orβ-oriented with respect to C-9 or C-11 respectively.

R₄ and/or R₅ independently indicate a hydrogen atom, a lower alkyl groupor a halogen atom. In case of a lower alkyl group, methyl group isespecially preferred, and in case of halogen a fluorine atom isespecially preferred. The compound in which at least one of R₄ and R₅ isa metyl or a fluorine atom is important. Both R₄ and R₅ may indicate thesame substituents.

R₆ is an alkyl consisted of 4 to 9 carbons, which may contain sidechains, a double bonds or alkoxy substituents. The alkoxy substituentsinclude such as methoxy, ethoxy and the like. Especially, n-alkyl groupsconsisted of 5 to 8 carbons preferred, and a n-alkyl group of 6 carbonsis particularly important. Alternatively, R₆ is the group shown in theformula following: ##STR12## wherein Y indicates a bond with C-16 or anoxygen atom, R₇ is a hydrogen atom, halogen atom or halogenated alkylgroup. Preferably, Y, and R₇ are an oxygen atom, and a halogenated alkylgroup, respectively.

The typical compounds of the present invention are, for example;

carbonylic acid esters of 13,14-dihydro-15-keto-PGF;

13,14-dihydro-15-keto-16R,S-fluoro-PGFs;

13,14-dihydro-15-keto-16,16-difluoro-PGFs;

13,14-dihydro-15-keto-16R,S-methyl-PGFs;

13,14-dihydro-15-keto-16,16-dimethyl-PGFs;

13,14-dihydro-15-keto-17S-methyl-PGFs;

13,14-dihydro-15-keto-9β-PGFs;

13,14-dihydro-15-keto-11β-PGFs;

13,14-dihydro-15-keto-11-dehydroxy-11R-methyl-PGFs;

13,14-dihydro-15-keto-11-dehydroxy-11R-hydroxymethyl-PGFs;

13,14-dihydro-15-keto-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGFs;

13,14-dihydro-15-keto-20-methoxy-PGFs;

13,14-dihydro-15-keto-20-methyl-PGFs;

13,14-dihydro-15-keto-20-ethyl-PGFs;

13,14-dihydro-15-keto-20-n-propyl-PGFs;

13,14-dihydro-15-keto-20-n-butyl-PGFs;

13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-PGFs;

13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGFs;

13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-11-dehydroxy-11R-methyl-PGFs;

13,14-dihydro-15-keto-16-desbutyl-16-trifluoromethylphenoxy-PGFs.

Though PGFs are usually named according to the skeleton of prostanoicacid as named hereinbefore, these may be named based on IUPACnomenclature. According to it, for example, PGF₁ α is nominated as7-[(1R,2R,3R,5S)-3,5-dihydroxy-2{(E)-(3S)-3-hydroxy-1-octenyl}-cyclopentyl]heptanoicacid; PGF₂ α is

(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-{(E)-(3S)-3-hydroxy-1-octenyl}-cyclopentyl]-5-heptenoicacid;

13,14-dihydro-15-keto-20-ethyl-PGF₂ α isopropyl ester isisopropyl(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-{3-oxo-1-decyl}cyclopentyl]-hept-5-enoate;

and 13,14-diydro-15-keto-20-methyl-PGF₂ α methyl ester is methyl(Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-(3-oxo-1-nonyl)cyclopentyl}-kept-5-enoate.

13,14-Dihydro-15-keto-PGFs of the present invention rapidly shows greatvasopressor activity without ephemeral vasorelaxation which is inherentto PGFs. Further, they are found to show no effect on trachea, bronchusand intestine such as increase of airway resistance due to contractionof trachea, and abdominal pain or diarrhea due to contraction ofintestine, which are inherent to PGs, and found to have low toxicity.Therefore, they are extremely useful as a vasopressor. In addition,according to such vasopressor activity, they can be used as a remedy foressential hypotension, symptomatic hypotension, orthostatic hypotension,acute hypotension accompanied with various diseases and conditions, andcan be used as a adjunctive remedy for shock and the like.

In order to prepare 13,14-dihydro-15-keto-PGFs of the present invention,as shown in the attached sythetic charts, the commercially available(-)-Corey lactone (1) is used as the starting material and subjected toCollines oxidation to give aldehyde (2), which is allowed to react withdimethyl (2-oxoalkyl)phosphonate to give α,β-unsaturated ketone (3).After reduction, a carbonyl group of the resulting saturated ketone (4)is protected. An alcohol obtained after the removal of p-phenyl benzoylfrom ketone (4) is reprotected by THP, and lactone (7) is reduced tolactol, and then an α-chain is introduced by Wittig reaction.

13,14-Dihydro-15-keto-PGF₂ s in which --(X)-- is ##STR13## can beobtained after reduction of lactone (7) to lactol (8), which issubsequently reacted with (4-carboxybutyl)triphenylphosphorane, and13,14-dihydro-15-keto-PGF₁ s, in which --(X)-- is ##STR14## can beobtained after hydrogenation of 13,14-dihydro-15-keto-PGF₂ s.

13,14-Dihydro-6,15-diketo-PGF₁ s in which --(X)-- is ##STR15## can beobtained by treating bromo- or iodo- ether obtained after cyclizationbetween C-5, -6-double bond shown below ##STR16## and the hydroxyl groupon C-9 using N bromosuccinimide or iodine, that is to say, addition of abromine atom or an iodine atom on C-5 and simultaneous cyclizationbetween C-6 and the hydroxyl group on C-9, with DBU, and hydrolysis ofthe resulting enol ether with acid to produce 6-keto group.

The synthesis of 13,14-dihydro-15-keto-5,6-dehydro-PGF₂ s in which (X)is ##STR17## involves 1,4-addition of monoalkylcopper complex ordialkylcopper complex of the following formulae; ##STR18## to4R-t-butyldimethylsilyloxy-2-cyclopenten-1-one, alkylation of theresulting copper enolate after 1,4-addition with6-alkoxycarbonyl-1-iodo-2-hexyne or its derivatives, and reduction ofthe resulting 13,14-dihydro-15-keto-PGE₂ types, for example, with sodiumborohydride.

13,14-Dihydro-15-keto-PGF in which R₃ is a methyl group can be obtainedafter reacting PGA types, which can be prepared by Jones oxidation ofthe hydroxyl group or C - 9 of 11-tosylate derivatives of PGF types,with dimethylcopper complex, and by reducing the resulting 11α-methyl-PGE₂ with sodium borohydride. Alternatively, it can be obtained byprotecting the carbonyl group of the saturated ketone (4) prepared afterreduction of the unsaturated ketone (3), converting the alcohol obtainedafter removal of p-phenylbenzoyl group from the saturated ketone (4) tothe corresponding tosylate, treating the tosylate with DBU, convertingthe resulting unsaturated lactone to the corresponding lactol,introducing an α-chain by Wittig reaction, oxidizing the resultingalcohol (9-position) to the corresponding PGA, reaction of the product(PGA) with dimethylcopper complex to introduce a methyl group at the11-position, and reducing the resulting 11-methyl PGE with, for example,sodium borohydride.

13,14-Dihydro-15-keto-PGFs in which R₃ ' is a hydroxymethyl group can besynthesized by adding methanol to thus obtained corresponding PGA typesusing benzophenone as a photosensitizer and reducing the resulting11-hydroxymethyl PGE type, for example, with sodium borohydride.

13,14-Dihydro-15-keto-PGFs in which either R₄ or R₅ is other than ahydrogen atom and R₆ is other than n-butyl may be obtained by using thecorresponding dimethyl (2-oxoalkyl)phospnonate to obtain α,β-unsaturatedketone (3). For example, 13,14-dihydro-15-keto-PGFs in which R₄ is afluorine atom, R₆ is n-butyl, and R₅ is a hydrogen atom, can be obtainedby using dimethyl (3-fluoro-2-oxoheptyl)phosphonate, and those whereinR₄ and R₅ are both hydrogen atoms and R₆ is hexyl, may be obtained byusing dimethyl (2-oxononyl)phosphonate.

The synthetic methods of the compounds in the present invention may notbe limited to ones described above, and the suitable means forprotection of the respective functional groups, oxidation, reduction andthe like may be optionally employed.

Prostaglandins F of the present invention can be used as medicaments foranimal and human, and, in general, used for systemic or localapplication by oral administration, intravenous injection, subcutaneousinjection and the like. The dosage varies depending on animal, human,age, weight, conditions, therapeutic effect, administration route,treatment time and the like.

The solid composition for oral administration of the present inventionincludes tablets, powder, granules and the like. In such solidcomposition, one or more active ingredient may be mixed with at leastone inactive diluent, for example, lactose, mannitol, glucose,hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate and the like. According tothe conventional manner, the composition may contain additives otherthan inactive diluent, for example, lubricant such as magnesiunstearate, disintegrant such as fibrous calcium gluconate, stabilizersuch as etherfied cyclodextrin such as α, β- or γ-cyclodextrin,dimethyl-α-, dimethyl-β-, trimethyl-β- or hydroxypropyl-β-cyclodextrin,branched cyclodextrin such as glucosyl-, maltosyl-cyclodextrin,formulated cyclodextrin, cyclodextrin containing sulfur, mitthoprotol,phospholipid and the like. When the above cyclodextrins are used,clathrate compound with cyclodextrin may be often formed to enhancestability. Alternatively, phospholipid may be used to form liposome,often resulting in enhanced stability.

Tablets or pills may be coated with film soluble in the stomach orintestine such as suger, gelatin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose phthalate and the like, or with more thantwo layers. Further, they may be formed as capsules with absorbablesubstances such as gelatin.

Liquid composition for oral administration may contain pharmaceuticallyacceptable emulsion, solution, suspension, syrup, elixyr as well asgenerally used inactive diluent, for example, purified water, ethanol,vegetable oil such as coconut oil. Such composition may containadjuvants such as wetting agent and suspension, sweetening agent,flavoring agent, preservatives and the like other than inactive diluent.Such liquid composition may be used by directly enclosing in softcapsules.

Other compositions for oral administration, which may contain one ormore active ingredient, include spray formulated by known method.

Injection for parenteral administration according to the presentinvention includes steril, aqueous or nonaqueous solution, suspension,emulsion and detergent.

Such aqueous solution and suspension include, for example, injectabledistilled water, physiological saline and Ringer. Non-aqueous solutionand suspension include, for example, propylene glycol, polyethyleneglycol, vegetabel oil such as olive oil, alcohols such as ethanol,polysorbate and the like. Such composition may contain adjuvants such aspreservatives, wetting agent, emulsifier, dispersant and the like. Theseare sterlized, for example, by filtration through bacteria-holdingfilter, compounding with germicides or irradiation of UV rays. These maybe used by producing sterile solid composition and dissolving in sterilewater or sterile solvent for injection before use.

The present invention will be illustrated in the following example.

EXAMPLE 1 (1) synthesis of dimethyl(7-methoxy-2-oxoheptyl)phosphonate##STR19## (1-1) Methyl 6-methoxy-caproate

Sodium hydride (NaH) (50%, 6.12 g) suspended in tetrahydrofuran (THF)(60 ml) was added to a solution of 1,6-hexanediol (15.0 g) in THF (200ml), and kept at 60° C. until gas evolution stopped. After cooling, asolution of methyl iodide (12 ml) in THF (35 ml) was added and keptovernight at room temperature The crude product obtaind after the usualwork-up was chromatographed to give 6-methoxy-1-hexanol. Yield; 8.16 g

6-Methoxy-hexanol (8.16 g) was oxidized with Jones reagent (2.67-M, 53ml) in acetone (100 ml) at -10° C. to give 6.17 g of 6-methoxy-caproicacid.

6-Methoxy-caproic acid (6.17 g) was dissolved in dry methanol (90 ml)containing hydrogen chloride (catalytic amount) and held overnight atroom temperature. The solvent was distilled off from the reactionsolution under reduced pressure to give methyl 6-methoxy-caproate.Yield; 5.68 g

(1-2) Dimethyl (7-methoxy-2-oxoheptyl)phsophonate

A solution of dimethyl methylphosphonate (8.88 g)in THF (60 ml) wascooled to -60 ° C., to which n-butylithium (1.55 - M, 46.2 ml) was addeddropwise. After addition, the solution was stirred at -60° C. for 30minutes. A solution of methyl 6-methoxy-caproate (5.65 g) in THF (50 ml)was added dropwise to the resulting solution and held at -60° C.overnight, and at room temperature for 2 hours. After the reactionsolution was cooled to 0° C., the reaction was neutralized by additionof acetic acid (4 ml). The crude product obtained after the usualwork-up was chromatographed (dichloromethane/methanol (5%)).

(2) Synthesis of dimethyl (2-oxononyl)phosphonate ##STR20##

A solution of dimethyl methylphosphoanate (24.3 ml) in THF (500 ml) wascooled to -78° C., to which n-butyllithium (1.6 - M, 136 ml) was addeddropwise After addition, the solution was stirred for one hour, and thenethyl octanoate (28.5 ml) was added dropwise. The reaction was stirredat -78° C. for 10 hours. Acetic acid (12.5 ml) was added to the reactioncooled at 0° C., and the solution was brought to room temperature andconcentrated under reduced pressure. The residue was diluted with ethylacetate, and the solution was washed with brine and dried. The crudeproduct obtained after concentration under reduced pressure waschromatographed (hexane/ethyl acetate=1/1) to give dimethyl(2-oxononyl)phosphonate. Yield; 30.2 g (83%)

(3) Synthesis of dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate##STR21## (3-1) Ethyl 2,2-dimethyl-caproate

A solution of isobutyric acid (45 g) in THF was added to LDA prepared at-78° C. according to the conventional manner and stirred for one hour. Asolution of butyl iodine (107 g) in dry HMPA was added, and stirred at-78° C. for one hour, and at room temperature for additional one hour.The crude product obtained after the conventional work-up was distilled.

Yield; 50 g (75%), b.p.; 68°/25 mmHg

(3-2) Dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate

A solution of dimethyl methylphosphonate (35.0 ml) in THF (300 ml) wascooled to -78° C., to which n-butyllithium (1.6 - M, 196 ml) was addeddropwise. After stirring at -78° C. for one hour, a solution of ethyl2,2-dimethylcaproate (27 g) in dry THF was added. The reaction solutionwas stirred at -78° C. for one hour, and then at room temperature foradditional 2 hours. The reaction solution was cooled to 0° C. and aceticacid (18 ml) was added thereto. The crude product obtained after theconventional work-up was distilled under reduced pressure and theresulting fraction (>130° C.) was chromatographed to give dimethyl(3,3-dimethyl-2-oxoheptyl)phosphonate. Yield, 9.72 g (26%)

(4) Synthesis of dimethyl (3-fluoro-2-oxoheptyl)phosphnate (4-1) Methyl2-fluorocaproate ##STR22##

Methyl 2-bromocaproate (40 g) was added to anhydrous potassium fluoride(23 g) in acetamide (23 g) kept at 105° C. The mixture was vigorouslystirred at 105° C. for 6 hours. The crude product obtained after theconventional work-up was distilled. Yield; 20 g (71 %), b.p.; 66° C./20mmHg

(4-2) Dimethyl (3-fluoro-2-oxoheptyl)phosphonate

Dimethyl methylphosphonate (8.38 g) was dissolved in dry THF (250 ml)and cooled to -78° C. n-Butyllithium (1.6-M, 42 ml) was added dropwise,and the reaction was stirred for 10 minutes. The above methylfluorocaproate (200 g) in THF (10 ml) was added dropwise. Afteraddition, the mixture was stirred at -78° C. for 45 minutes, and then atroom temperature for additional 45 minutes. The crude product obtainedafter the conventional work-up was chromatographed (hexane/ethylacetate=1/1). Yield; 5.04 g (62 g)

(5) Synthesis of dimethyl (4S)-methyl-2-oxoheptylphosphonate ##STR23##(5-1) Ethyl 3S-methyl-caproate

Sodium ethoxide was prepared from sodium metal (7.61 g) in absolutemethanol (200 ml). Diethyl malonate (50.3 ml) was added dropwise, andthe solution was heated to 80° C. 2-Bromopentane (50 g) was added andthe resultant was refluxed for 24 hours. According to the conventionalwork-up, diethyl (2-pentyl)-malonate (62.7 g) was obtained. Diethyl(2-pentyl)malonate was added to 50% aqueous solution of potassiumhydroxide, and heated for 3 hours while water/ethanol was distilled off.After cooling, the resultant was acidified with concentratedhydrochloric acid, and subsequently extracted with ethyl acetate. Theproduct obtained after concentration under reduced pressure was heatedat 180° C. until gas evolution stopped. After distillation, colorless3R,S-methyl-caproic acid was obtained. Yield; 27.7 g (35%), b.p. >200°C./760 mmHg

3R,S-Methyl-caproic acid (27.7 g) was dissolved in ethanol (160 ml), andcinchonidine (64 g) was dissolved thereto with heating. The saltobtained after concentration under reduced pressure was recrystallizedsix times from 60% methanol to give colorless needlelike crystals.Yield; 14.4 g, [α]_(D) ³¹° =-3.3° (c=13.6 in benzene, lit. -3.1°)

The above 3S-methyl-caproic acid (3.94 g) was converted into ethyl esterusing ethanol and catalytic amount of sulfuric acid. Yield; 4.04 g (84%)

(5-2) Dimethyl (4S-methyl-2-oxoheptyl)phosphonate

The title compound was synthesized according to the conventional methodwith using ethyl 3S-methyl-caproate and dimethyl methylphosphonate.

EXAMPLE 2 (cf. SYNTHETIC SCHEME I) Synthesis of13,14-dihydro-15-keto-PGF₂ α ehtyl ester (11); R=Et (2-1) Synthesis of1S-2-oxa-3-oxo-6R-(3-oxo-1-trans-octenyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)-octane(3)

Dimethyl (2-oxoheptyl)phosphonate (8.9 ml) was added dropwise to asuspension of NaH (60%, 1.76 g) in THF (200 ml) and stirred for 30minutes. To the generated phosphonate anion was added aldehyde (2) inTHF (400 ml), which was obtained by Collins oxidation of (-)-Coreylactone (1) (15 g). The reaction solution was kept overnight at roomtemperature and acetic acid was added thereto. After the usual work-up,α,β-unsaturated ketone (3) was obtained. Yield; 11.8 g (62%)

(2-2) Synthesis of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxyoctyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo-(3,3,0)octane(5)

The unsaturated ketone (3) (11.8 g) was hydrogenated with using 5%palladium/carbon (0.300 g) in ethyl acetate (100 ml) to give ketone (4).The ketone (4) (11.8 g) was dissolved in toluene (200 ml), to which wereadded ethylene glycol and p-toluenesulfonic acid (catalytic amount). Thesolution was refluxed overnight while water produced was azeotropicallydistilled off. After the usual work-up, ketal (5) was obtained. Yield;11.8 g (91%)

(2-3) Synthesis of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-1-octyl)-7R-hydroxy-cis-bicyclo-(3,3,0)octane(6)

The compound (5) (11.8 g) was dissolved in methanol (100 ml) and THF (20ml), and potassium carbonate (3.32 g) was added thereto. The reactionmixture was stirred at room temperature for 7 hours. The crude productobtained after the usual work-up was chromatographed (ethylacetate/hexane=1/3-1/1) to give alcohol (6). Yield; 6.78 g (90%)

(2-4) Synthesis of tetrahydropyranyl ether (7)

To the dichloromethane solution (100 ml) of the compound (6) (6.78 g)was added dihydropyran (4 ml) and p-toluenesulfonic acid (catalyticamount). The reaction was stirred for 20 minutes. After the usualwork-up, the resulting crude product was chromatographed (ethylacetate/hexane=2/1) to yield the tetrahydropyranyl ether (7). Yield;8.60 g (100%)

This operation was repeated and 14.67 g of the product in total wasobtained.

(2-5) Synthesis of lactol (8)

Diisobutylaluminium hydride (DIBAL-H) (1.5-M, 50 ml) was added dropwiseto the tetrahydropyranyl ether (7) (14.67 g) in dry toluene (100 ml) at-78° C. and stirred for 60 minutes. After the usual work-up, lactol (8)was obtained.

(2-6) Synthesis of13,14-dihydro-11-(2-tetrahydropylanyl)oxy-15,15-ethylenedioxy-PGF₂ α(9)

Sodium hydride (60%, 11.1 g) washed with pentane was suspended in DMSO(150 ml), and stirred at 60°-70° C. for 3 hours. The generated sodiummethylsulfinyl carbanion was cooled, and(4-carboxybutyl)tripheylphosphonium bromide (65.6 g) in DMSO was addedto the carbanion solution. The reaction mixture was stirred for 30minutes. The lactol (8) in DMSO (80 ml) was added to the generatedylide. After stirring overnight, the reaction solution was poured ontoice/water, and the pH value was adjusted to 12 with 5% sodium hydroxidesolution and extracted with ether. The aqueous layer was adjusted to pH4-5 with 4N hydrochloric acid and extracted with ethyl acetate. Thecommbined ethyl acetate layers were washed with brine, and dried overmagnesium sulfate. The solvent from the ethyl acetate extracts wasdistilled off under reduced pressure to leave a crude product. The crudeproduct was dissolved into ether, and the insoluble matters werefiltered off, and the filtrate was concentrated under reduced pressureto give the compound (9 ). Yield; 15.17 g (85%)

(2-7) Synthesis of 13,14-dihydro-11-(2-tetrahydropylanyl)oxy-15,15-ethylenedioxy-PGF₂ α ethyl ester (10)

Carboxylic acid (9) (12.1 g) was treated by DBU (4.9 ml) and ethyliodide (2.4 ml) in anhydrous acetonitrile (100 ml) at 60° C. for 2hours. The crude product obtained after the usual work-up waschromatographed (ethyl acetate/hexane=1/3) to give ethyl ester (10).Yield, 8.52 g (63%)

(2-8) Synthesis of 13,14-dihydro-15-keto-PGF₂ α ethyl ester (11)

The compound (10) (0.200 g) in a mixed solvent (acetic acid/THF/water=3/1/1) (5 ml) was kept at 50° C. for 4 hours. The solvent wasdistilled off under reduced pressure, and the resulting crude productwas chromatographed (ethyl acetate/hexane=2/1) to give13,14-dihydro-15-keto-PGF₂ α ethyl ester (11). Yield, 0.054 g (41%)

NMR spectrum of 13,14-dihydro-15-keto-PGF₂ α ethyl ester (11) is shownin FIG. 1. Mass (SIMS) m/z 383 (M+1), 365 (M+1-18)

EXAMPLE 3 (cf. Synthetic scheme I) Synthesis of13,14-dihydro-15-keto-PGF₂ α methyl ester (11); R=Me

In the same manner as described in Example 2, except that carboxylicacid (9) was converted into the corresponding methyl ester (10) withdiazomethane, 13,14-dihydro-15-keto-PGF₂ α methyl ester (11) wassynthesized.

NMR spectrum of 13,14-dihydro-15-keto-PGF₂ α methyl ester (11) is shownin FIG. 2. Mass (SIMS) NaCl added, m/z 391 (m⁺ +Na), 351 (m+1-18)

EXAMPLE 4 (cf. Synthetic scheme I) Synthesis of13,14-dihydro-15-keto-PGF₁ α ethyl ester (13); R=Et (4-1) Synthesis of13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropylanyl)oxy-PGF₁ αethyl ester (12)

13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropylanyl)oxy-PGF₂ αethyl ester (10) (3.50 g) was hydrogenated with using platinum oxide inethanol (150 ml) and hydrogen. After the usual work-up,13,14-dihydro-15,15-ethylenedioxy-11-(2-tetrahydropyranyl)oxy-PGF₁ αethyl ester (12) (3.50 g) was obtained.

(4-2) Synthesis of 13,14-dihydro-15-keto-PGF₁ α ethyl ester (13)

Dihydro-PGF₁ α derivative (12) (0.10 g) in a mixed solvent (aceticacid/water/THF=3/1/1) (10 ml) was kept at 50° C. for 6 hours. Thesolvent was distilled off under reduced pressure, and the resultingcrude product was chromatographed (ethyl acetate/hexane=2/1) to give13,14-dihydro-15-keto-PGF₁ α ethyl ester (13). Yield; 0.0455 g (61%)

NMR spectrum of 13,14-dihydro-15-keto-PGF₁ α ethyl ester (13) is shownin FIG. 3.

EXAMPLE 5 (cf. Synthetic scheme II) Synthesis of13,14-dihydro-15-keto-16R,S-fluoro-PGF₂ α methyl ester (26) (5-1)Synthesis of1S-2-oxa-3-oxo-6R-(4R,S-fluoro-3-oxo-1-trans-octenyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(14)

Dimethyl (3R,S-fluoro-2-oxoheptyl)phosphonate(10.23 g) in THF was addedto sodium hydride suspension in THF, and the mixture was stirred for 20minutes at room temperature. To the above mixture was added the THFsolution of aldehyde (2) obtained after Collins oxidation of (-)-Coreylactone (1) (15.00 g). After stirring at room temperature for 2 hours,the reaction solution was neutralized with acetic acid (15 ml).Subsequently, the residue obtained after the usual work-up waschromatographed (ethyl acetate/hexane=1/2) to give enone (14). Yield;10.45 g (53%)

(5-2) Synthesis of1S-2-oxa-3-oxo-6R-(4R,S-fluoro-3R,S-hydroxy-1-octyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(16)

Enone (14) (10.45 g) was hydrogenated in ethyl acetate (50 ml) using 5%palladium/carbon (1.0 g) and hydrogen to give ketone (15). Yield; 9.35 g(89%)

Ketone (15) (9.35 g) was reduced in absolute methanol (200 ml) withusing sodium borohydride (1.15 g) to give colorless oil (16). Yield,6.50 g (69%)

(5-3)1S-2-oxa-3-oxo-6R-(4R,S-fluoro-3R,S-t-butyldimethylsilyloxy-1-octyl)-7R-hydroxy-cis-bicyclo(3,3,0)octane(18)

Alcohol (16) (6.50 g) was converted to the correspondingt-butyldimethylsilyl ether (17) in anhydrous DMF (30 ml) witht-butyldimethylsilyl chloride (6.27 g) and imidazole (5.67 g). Yield;8.80 g (100%)

t-Butyldimethylsilyl ether (17) (8.80 g) was dissolved in methanol (80ml). Anhydrous potassium carbonate (2.09 g) was added to the solution.After the reaction solution was stirred at room temperature for 4 hours,alcohol (18) as colorless oil was obtained after the conventionaltreatment. Yield; 4.11 g (67%)

(5-4) Synthesis of13,14-dihydro-16R,S-fluoro-15R,S-t-butyldimethylsilyloxy-11R-(2-tetrahydropyranyl)oxy-PGF₂α methyl ester (22)

Alcohol (18) (4.11 g) was treated with dihydropyran (4.10 ml) andp-toluenesulfonic acid (catalitic amount) in dichloromethane (50 ml) atroom temperature for 10 minutes. After the usual work-up, the obtainedresidue was chromatographed (ethyl acetate/hexane=1/4-1/3) to givetetrahydropyranyl ether (19) as a colorless oil. Yield; 5.08 g (100%)

Tetrahydropyranyl ether (19) (5.08 g) was reduced with DIBAL-H (1.5-M,20 ml) in anhydrous toluene (60 ml) at -78° C. to give lactol (20) as acolorless oil.

According to the conventional method, ylide was prepared from(4-carboxybutyl)triphenylphosphonium bromide (18.51 g), and previouslyprepared lactol (20) DMSO was added thereto. The resultant was stirredat room temperature for 2.5 hours. After the usual work-up, the obtainedcrude product was dissolved in ether, the insoluble matters werefiltered off, and the filtrate was concentrated under reduced pressureto give a crude carboxylic acid (21). Yield; 8.0 g

The crude carboxylic acid (21) (2.00 g) was converted to thecorresponding methyl ester (22) in ether with diazomethane. The crudeproduct obtained after the usual work-up was chromatographed (ethylacetate/hexane=1/4-1/3) to give13,14-dihydro-16R,S-fluoro-15R,S-t-butyldimethylsilyloxy-11R-(2-tetrahydropyranyl)oxy-PGF₂α methyl ester (22) (0.550 g).

(5-5) Tetrahydropyranyl ether formation of the compound (22) Synthesisof bis-tetrahydropyranyl ether (23)

Alcohol (22) (0.550 g) was treated in anhydrous dichloromethane (30 ml)with dihydropyran (0.5 ml) and several pieces of p-toluenesulfonic acidat room temperature for 30 minutes. The crude product obtained after theusual work-up was chromatographed (ethyl acetate/hexane=1/6-1/3) to givebis-tetrahydropyranyl ether (23) as a colorless oil. Yield; 0.580 g(92%)

(5-6) Synthesis of 13,14-dihydro-15-keto-16R,S-fluoro-PGF₂ α methylester (26)

Bis-tetrahydropyranyl ether (23) (0.580 g) was treated overnight inanhydrous THF (20 ml) with tetrabutylammonium fluoride (1.0-M, 10 ml) atroom temperature. The crude product obtained after the usual work-up waschromatographed (ethyl acetate/hexane=1/3-1/2) to give alcohol (24) as acolorless oil. Yield; 0.300 g (62%)

Alcohol (24) (0.300 g) was oxidized with Jones reagent (2.67-M, 1.04 ml)in acetone (20 ml) at -10° C. The crude product obtained after the usualwork-up was chromatographed (ethyl acetate/hexane=2/7) to give ketone(25) as a colorless oil. Yield; 0.280 g (94%)

Ketone (25) (0.280g) in a mixed solvent (acetic acid/water/THF=10/3.3/1)(25 ml) was kept at 55° C. for 2 hours. The solvent was distilled offunder reduced pressure and the resulting crude product waschromatographed (ethyl acetate/hexane=2/3-1/1) to give13,14-dihydro-15-keto-16R,S-fluoro-PGF₂ α methyl ester (26). Yield;0.123 g (63%)

NMR spectrum of 13,14-dihydro-15-keto-16R,S-fluoro-PGF₂ α methyl ester(26) is shown in FIG. 4. Mass (SIMS) m/z 387 (M⁺ +1), 349 (M⁺ +1-18)

EXAMPLE 6 (cf. Synthetic scheme III) Synthesis of13,14-dihydro-15-keto-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGF₂ αmethyl ester (37) (6-1)15R,S-t-Butyldimethylsilyloxy-13,14-dihydro-16R,S-fluoro-PGF₂ α methylester (29)

Lactone (18) (2.313 g) obtained according to Example 5 was reduced intoluene (25 ml) with using DIBAL-H (1.5-M, 15 ml) at -78° C. to givelactol (27) as a colorless oil.

Sodium hydride (60%, 1.84 g) washed with dry ether was suspended inanhydrous DMSO (20 ml), and kept at 70° C. for one hour to generatesodium methylsufinyl carbanion. A solution of(4-carboxybutyl)triphenylphosphonium bromide (10.19 g) in DMSO (30 ml)was added to the generated carbanion cooled at room temperature andstirred at room temperature for 10 minutes to yield ylide. To the ylidewas added above lactol (27) in DNSO (50 ml) and stirred for 2.5 hours.The crude product obtained after the usual work-up was converted to thecorresponding methyl ester with diazomethane, subsequentlychromatographed (ethyl acetate/hexane=2/3-3/2) to give ester (29) as acolorless oil. Yield; 1.00 g (34%)

(6-2) Synthesis of15R,S-t-butyldimethylsilyloxy-13,14-dihydro-16R,S-fluoro-11R-p-toluenesulfonyloxy-PGF₂α methyl ester (30)

15R,S-t-Butyldimethylsilyloxy-13,14-dihydro-16R,S-fluoro-PG₂ α methylester (29) (0.430 g) was treated in anhydrous pyridine (20 ml) withp-toluenesulfonyl chloride (3.01 g) at room temperature for 2.5 hours.The crude product obtained after the usual work-up was chromatographed(ethyl acetate/hexane=1/3) to give the tosylate (30) as a colorless oil.Yield; 0.417 g (74%)

(6-3) 15R,S-t-Butyldimethylsilyloxy-13,14-dihydro-16R,S-fluoro-PGAmethyl ester (31)

The tosylate (30) (0.417 g) was oxidized with Jones reagent (2.67-M, 0.9ml) in acetone (25 ml) at -20° C. The crude product obtained after theusual work-up was chromatographed (ethyl acetate/hexane=1/5) to give aPGA derivative (31) as a colorless oil. Yield; 0.234 g (75%)

(6-4) Synthesis of15R,S-t-butyldimethylsilyloxy-13,14-dihydro-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGE₂methyl ester (32)

Copper iodide (0.233 g) was suspended in anhydrous ether (30 ml), towhich was added dropwise methyllithium (1.5-M, 1.56 ml) at -10° C. Asolution of the enone (31) (0.281 g) in anhydrous ether (20 ml) wasadded to the above mixture. After stirring at -10° C. for 40 minutes,acetic acid (0.6 ml) was added to stop the reaction. The crude productobtained after the usual work-up was chromatographed (ethylacetate/hexane=1/7) to give a 11R-methyl compound (32) as a colorlessoil. Yield; 0.192 g (66%)

(6-5) Synthesis of15R,S-t-butyldimethylsilyloxy-13,14-dihydro-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGF₂α methyl ester (33)

11R-Methyl-PGE₂ derivative (32) (0.234 g) was reduced in dry methanol(15 ml) with using sodium borohydride (0.178 g) at 0° C. The crudeproduct obtained after the usual work-up was chromatographed (ethylacetate/hexane=1/4) to give 9α-hydroxy derivative (33) as a colorlessoil. Yield; 0.133 g (57%)

(6-6) 13,14-Dihydro-16R,S-fluoro-15-keto-11R-dehydroxy-11R-methyl-PGF₂ αmethyl ester (37)

9α-Hydroxy derivative (33) (0.302 g) was converted to the correspondingtetrahydropyranyl ether (34) according to the conventional manner.Yield; 0.352 g (100%)

11R-Methyl-PGF₂ α derivative (34) (0.353 g) was converted to alcohol(35) with using tetrabutylammonium fluoride (1-M, 4 ml) in anhydrous THF(15 ml). Yield; 0.261 g (92%)

Alcohol (35) (0.261 g) was oxidized with Jones reagent (2.67-M, 0.5 ml)in acetone (15 ml) at -15° C. The crude product obtained after the usualwork-up was chromatographed (ethyl acetate/hexane=1/7) to give ketone(36). Yield; 0.262 g (87%)

Ketone (36) (0.226 g) in a mixed solvent (aceticacid/water/THF=10/3.3/1) (20 ml) was kept at 45°-50° C. for 3 hours. Thesolvent was concentrated under reduced pressure and the resulting crudeproduct was chromatographed (ethyl acetate/hexane=1/3) to give13,14-dihydro-15-keto-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGF₂ αmethyl ester (37). Yield; 0.171 g (92%)

NMR spectrum of13,14-dihydro-15-keto-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGF₂ αmethyl ester (37) is shown in FIG. 5. Mass (SIMS) m/z 385 (m⁺ +1), 367(M⁺ +1-18)

EXAMPLE 7 (cf. Synthetic scheme IV) Synthesis of13,14-dihydro-15-keto-20-ethyl-PGF₂ α methyl ester (45); R=Me (7-1)1S-2-oxa-3-oxo-6R-(3-oxo-1-trans-decenyl)-7R-(4-phenylbenzoyloxy)-cis-bicyclo(3,3,0)octane(38)

The solution of dimethyl (2-oxononyl)phosphonate (3.50 g) in dry THF (50ml) was added dropwise to NaH (60%, 0.570 g) in THF (100 ml) and thereaction mixture was stirred for 40 minutes. A THF solution (60 ml) ofaldehyde (2) obtained from (-)-Corey lactone (1) was added dropwise tothe phosphonate anion in THF. After stirring overnight, acetic acid (5ml) was added under ice-cooling and the compound (38) was obtainedaccording to the conventional manner.

(7-2) Synthesis of1S-2-oxa-3-oxo-6R-(3-oxo-1-decyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(39)

Unsaturated ketone (38) was hydrogenated in ethyl acetate (150 ml) withusing 5% palladium/carbon (0.120 g) to give the compound (39).

(7-3) Synthesis of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-1-decyl)-7R-(4-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(40)

Saturated ketone (39), ethylene glycol (10 ml) and p-toluenesulfonicacid (catalytic amount) were dissolved in benzene (200 ml), and thesolution was heated at reflux for 24 hours using a Dean-Stark Trap.After the usual work-up, the compound (40) was obtained. Yield; 3.90 g(53% based on the compound (1))

(7-4) Synthesis of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-1-decyl)-7R-hydroxy-cis-bicyclo(3,3,0)octane(41)

Ketal (40) (3.90 g) was dissolved in dry methanol (150 ml) and stirredwith potassium carbonate (1.30 g) for 6 hours. Acetic acid (0.9 g) wasadded while cooling with ice. The crude product obtained after the usualwork-up was chromatographed to give the compound (41). Yield; 2.18 g(85%)

(7-5) Synthesis of 20-ethyl-15,15-ethylenedioxy-13,14-dihydro-PGF₂ αmethyl ester (44)

Lactone (41) (1.22 g) was reduced in dry toluene (30 ml) with usingDIBAL-H (7.6 ml) at -78° C. After stirring for 45 minutes, methanol (10ml) was added and the mixture was stirred at room temperature for 30minutes. The reaction solution was diluted with ether and filtered. Thefiltrate was concentrated under reduced pressure to give lactol (42).

Sodium hydride (60%, 1.15 g) washed with dry ether was suspended in DMSO(30 ml) and kept at 65°-70° C. for one hour to generate methylsulfinylcarbanion. A solution of (4-carboxybutyl)triphenylphosphonium bromide(6.4 g) in DMSO was added to the carbanion at room temperature togenerate ylide, and the solution was stirred for 40 minutes. Lactol (42)in DMSO was added dropwise and the resultant was stirred overnight. Thesolution was poured into ice/water, the pH value was adjusted to 12 withaqueous potassium carbonate and the resultant was extracted with ethylacetate. The aqueous layer was adjusted to pH 4 with dilutedhydrochloric acid while cooling with ice and extracted with ether. Thecombined ether layers were dried and concentrated under reduced pressureto give the compound (43). The crude product (43) was converted into thecorresponding methyl ester (44) with diazomethane, which waschromatographed. Yield; 1.29 g (82%)

(7-6) Synthesis of 13,14-dihydro-15-keto-20-ethyl-PGF₂ α methyl ester(45)

Ketal (44) (1.06 g) was dissolved in a mixed solvent (aceticacid/water/THF=3/1/1) (18 ml) and kept at 50° C. for 3 hours. Thesolvent was distilled off and the resulting crude product waschromatographed to give 20-ethyl-13,14-dihydro-15-keto-20-ethyl-PGF₂ αmethyl ester (45). Yield; 0.868 g (74%)

NMR spectrum of 13,14-dihydro-15-keto-20-ethyl-PGF₂ α methyl ester (45)is shown in FIG. 6.

EXAMPLE 8 Synthesis of 13,14-dihydro-16,16-dimethyl-15-keto-PGF₂ α ethylester (46) ##STR24##

In the same manner as described in Examples 1 to 713,14-dihydro-15-keto-16,16-dimethyl-PGF₂ α ethyl ester (46) wasobtained with using (-)-Corey lactone (1) and dimethyl(3,3-dimethyl-2-oxoheptyl)phosphonate.

NMR spectrum of 13,14-dihydro-15-keto-16,16-dimethyl-PGF₂ α ethyl ester(46) is shown in FIG. 7. Mass (DI) m/z 410, 392 (M⁺ -18), 374

EXAMPLE 9 Synthesis of 13,14-dihydro-15-keto-20-methoxy-PGF₂ α methylester (47) ##STR25##

In the same manner as described in Example 1 to 8,13,14-dihydro-15-keto-20-methoxy-PGF₂ α methyl ester (47) was preparedwith using (-)-Corey lactone (1) and dimethyl(7-methoxy-3-oxoheptyl)phosphonate.

NMR spectrum of 13,14-dihydro-15-keto-20-methoxy-PGF₂ α methyl ester(47) is shown in FIG. 8.

EXAMPLE 10 Synthesis of 13,14-dihydro-15-keto-17S-methyl-PGF₂ α ethylester (101) ##STR26##

In the same manner as described in Example 1 to 9,13,14-dihydro-15-keto-17S-methyl-PGF₂ α ethyl ester (101) was preparedwith using (-)-Corey lactone (1) and dimethyl(4S-methyl-2-oxoheptyl)phosphonate.

NMR spectrum of 13,14-dihydro-15-keto-17S-methyl-PGF₂ α ethyl ester(101) is shown in FIG. 9. Mass (DI) m/z 396 (M⁺), 378 (M⁺ -18), 360

EXAMPLE 11 (cf. Synthetic scheme IV) Synthesis of13,14-dihydro-15-keto-20-ethyl-PGF₂ α ethyl ester (45); R=Et

Procedure described in Example 7 was repeated to prepare20-ethyl-13,14-dihydro-15-keto-PGF₂ α ethyl ester (45), except thatcarboxylic acid (43) was converted into the corresponding ethyl ester(44) with using ethyl iodide and DBU in acetonitrile at 50° C.

NMR spectrum of 13,14-dihydro-15-keto-20-ethyl-PGF₂ α ethyl ester (45)is shown in FIG. 10. Mass (DI) m/z 410 (M⁺), 392 (M⁺ -18), 374

EXAMPLE 12 (cf. Synthetic scheme IV) Synthesis of13,14-dihydro-15-keto-20-ethyl-PGF₂ α isopropyl ester (45); R=iso-Pro

Procedure described in Example 7 was repeated, except that carboxylicacid (43) was converted into the corresponding isopropyl ester (44) withusing isopropyl iodide and DBU in acetonitrile at 50° C. and20-ethyl-13,14-dihydro-15-keto-PGF₂ α isopropyl ester (45) was obtained.

NMR spectrum of 13,14-dihydro-15-keto-20-ethyl-PGF₂ α isopropyl ester(45) is shown in FIG. 11. Mass (DI) m/z 424 (M⁺), 406 (M⁺ -18), 388, 347

EXAMPLE 13 (cf. Synthetic scheme IV) Synthesis of13,14-dihydro-15-keto-20-ethyl-PGF₂ α n-butyl ester (45); R=n-Bu

Procedure described in Example 7 was repeated to prepare20-ethyl-13,14-dihydro-15-keto-PGF₂ α n-butyl ester (45), except thatcarboxylic acid (43) was converted into the corresponding n-butyl ester(44) with using n-butyl iodide and DBU in acetonitrile at 50° C.

NMR spectrum of 13,14-dihydro-15-keto-20-ethyl-PGF₂ α n-butyl ester (45)is shown in FIG. 12. Mass (DI) 420 (M⁺), 402 (M⁺ -18), 376, 347

EXAMPLE 14 (cf. Synthetic scheme IV) Synthesis of13,14-dihydro-15-keto-20-ethyl-PGF₁ α methyl ester (48) ##STR27##

13,14-Dihydro-15-keto-20-ethyl-PGF₂ α methyl ester (45); R=Me, (0.0505g) was hydrogenated in ethanol with using PtO₂ to give13,14-dihydro-15-keto-20-ethyl-PGF₁ α methyl ester (48) (0.0166 g).

NMR spectrum of 20-ethyl-13,14-dihydro-15-keto-PGF₁ α methyl ester (48)is shown in FIG. 13. Mass (DI) m/z 398 (M⁺), 380 (M⁺ -18), 362, 349

EXAMPLE 15 (cf. Synthetic scheme V) Synthesis of13,14-dihydro-15-keto-20-ethyl-11R-dehydroxy-11R-methyl-PGF₂ α methylester (57) (15-1) Tosylation of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-1-decyl)-7R-hydroxy-cis-bicyclo(3,3,0)octane(41); synthesis of tosylate (49)

Alcohol (41) (1.723 g) was treated with p-toluenesulfonyl chloride(2.893 g) in pyridine (5 ml) at 0° C. to give tosylate (49). Yield;1.812 g (74%)

(15-2) Synthesis of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-1-decyl)-cis-bicyclo(3,3,0)-7-octene(50)

Tosylate (49) (1.812 g) was dissolved into toluene (1.9 ml) and DBU (5.6ml), and the solution was kept at 60° C. for 7 hours. The crude productobtained after the usual work-up was chromatographed (hexane/ethylacetate=3/1) to give olefin (50). Yield, 0.7594 g (63%)

(15-3) Reduction of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-1-decyl)-cis-bicyclo(3,3,0)-7-octene(50) with DIBAL-H; synthesis of lactol (51)

Olefin (50) (0.7594 g) was reduced with DIBAL-H (1.5-M, 6.2 ml) to givelactol (51).

(15-4) Synthesis of methyl 20-ethyl-15,15-ethylenedioxy-9S-hydroxy-cisΔ⁵-Δ¹⁰ -prostanoate (53)

Lactol (51) was allowed to react with ylide obtained from(4-carboxybutyl)triphenylphosphonium bromide and sodium methylsulfinylcarbanion in DMSO to give prostanoic acid (52). The resultant wasesterified with diazomethane to give the corresponding methylprostanoate (53). Yield, 0.6600 g (67%)

(15-5) Synthesis of 13,14-dihydro-20-ethyl-15,15-ethylenedioxy-PGA₂methyl ester (54)

Methyl prostanoate (53) (0.6600 g) was oxidized with Jones reagent inacetone (40 ml) at -20° C. After chromatography (hexane/ethylacetate=3/1), 13,14-dihydro-20-ethyl-15,15-ethylenedioxy-PGA₂ methylester (54) was obtained. Yield, 0.6182 g (99%)

(15-6) Synthesis of13,14-dihydro-20-ethyl-15,15-ethylenedioxy-11R-dehydroxy-11R-methyl-PGE.sub.2methyl ester (55)

Enone (54) (0.6100 g) was allowed to react with dimethylcopper complexobtained from copper iodide (0.8380 g) and methyllithium (1.5-M, 5.8 ml)in ether (15 ml) to give 13,14-dihydro-20-ethyl-15,15-ethylenedioxy-11R-dehydroxy-11R-methyl-PGE₂ methyl ester (55). Yield, 0.5720 g (94%)

(15-7) Synthesis of 13,14-dihydro-15-keto-20-ethyl-11R-methyl-PGF₂ αmethyl ester (57)

Ketone (55) (0.4023 g) was reduced with diisobutylaluminium(2,6-di-tert-butyl-4-methyl)-phenoxide in toluene to give alcohol (56).Alcohol (56) (0.2016 g) was kept in a mixed solvent (aceticacid/water/THF=3/1/1) (20 ml) at 50° C. for one hour. After the usualprocedure, 13,14-dihydro-15-keto-20-ethyl-11R-dehydroxy-11R-methyl-PGF₂α methyl ester (57) was obtained. Yield; 0.0960 g

NMR spectrum of13,14-dihydro-15-keto-20-ethyl-11R-dehydroxy-11R-methyl-PGF₂ α methylester (57) is shown in FIG. 14. Mass 394 (DI) m/z 394 (M⁺), 375 (M⁺-18), 358, 344

EXAMPLE 16 Synthesis of 13,14-dihydro-15-keto-20-n-butyl-PGF₂ α methylester (58) ##STR28##

In the same manner as described in Examples 7 to 14,13,14-dihydro-15-keto-20-n-butyl-PGF₂ α methyl ester (58) was obtainedwith using dimethyl (2-oxoundecyl)phosphonate prepared in the samemanner as preparation of dimethyl (2-oxononyl)phosphonate in Example 1and (-)-Corey lactone.

NMR spectrum of 13,14-dihydro-15-keto-20-n-butyl-PGF₂ α methyl ester(58) is shown in FIG. 15. Mass (DI) m/z 424, (M⁺), 406 (M⁺ -18), 388,375

EXAMPLE 17 Synthesis of 13,14-dihydro-15-keto-20-methyl-PGF₂ α methylester (59) ##STR29##

In the same manner as described in Examples 7 to 14 and 16,13,14-dihydro-15-keto-20-methyl-PGF₂ α methyl ester (59) was obtainedwith using dimethyl (2-oxooctyl)phosphonate prepared in the same manneras preparation of dimethyl (2-oxononyl)phosphonate in Example 1, and(-)-Corey lactone (1).

NMR spectrum of 13,14-dihydro-15-keto-20-methyl-PGF₂ α methyl ester (59)is shown in FIG. 16. Mass (SIMS) m/z 383 (M⁺ +1), 365 (M⁺ -18), 347

EXAMPLE 18 Synthesis of13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-11R-dehydro-11R-methyl-PGF.sub.2α methyl ester (60) ##STR30##

In the same manner as described in Example 6,13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-11R-dehydroxy-11R-methyl-PGF.sub.2α methyl ester (60) was obtained with using dimethyl(3R,S-fluoro-2-oxononyl)phosphonate prepared in the same manner assynthesis of dimethyl (3R,S-fluoro-2-oxoheptyl)phosphonate in Example 1,and (-)-Corey lactone.

NMR spectrum of13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-11R-dehydro-11R-methyl-PGF.sub.2α methyl ester (60) is shown in FIG. 17. Mass (DI) m/z 412 (M⁺), 394 (M⁺-18)

EXAMPLE 19 Synthesis of 13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-PGF₂α methyl ester (61) ##STR31##

In the same manner as described in Example 5,13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-PGF₂ α methyl ester (61) wasobtained with using dimethyl (3R,S-fluoro-2-oxononyl)phosphonate and(-)-Corey lactone.

NMR spectrum of 13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-PGF₂ αmethyl ester is shown in FIG. 18.

Mass (DI) m/z 414 (M⁺), 396(M⁺ -18), 378, 358

EXAMPLE 20 (cf. Synthetic scheme VI) Synthesis of13,14-dihydro-15-keto-9β,11α-PGF₂ methyl ester (64); R=CH₃

Alcohol (10) (0.2423 g) was converted into the corresponding benzoate(62) in dichloromethane (20 ml) with using diethyl azodicarboxylate(0.1026 g), benzoic acid (0.0720 g) and triphenylphosphine (0.1545 g).Yield; 0.1223 g

The above benzoate (62) was treated with potassium carbonate in methanolto give 9β,11α-PGF derivative (63). The obtained 9β,11α-hydroxy-PGFderivative is deketalized to 13,14-dihydro-15-keto-9β, 11α-PGF₂ methylester (64) Yield; 0.0236 g

NMR spectrum of 13,14-dihydro-15-keto-9β-11α-hydroxy-PGF₂ methyl ester(64); R=CH₃, is shown in FIG. 19.

Mass (DI) m/z 368 (M⁺), 350(M⁺ -18), 332, 319, 301

EXAMPLE 21 Synthesis of 13,14-dihydro-15-keto-20-n-propyl-PGF₂ α methylester (65) ##STR32##

In the same manner as described in Examples 7 to 14, 16 and 17,13,14-dihydro-15-keto-20-n-propyl-PGF₂ α methyl ester (65) was preparedwith using dimethyl (2-oxodecyl)phosphonate obtained in analogous to thesynthesis of dimethyl (2-oxononyl)phosphonate in Example 1, and(-)-Corey lactone (1).

NMR spectrum of 13,14-dihydro-15-keto-20-n-propyl-PGF₂ α methyl ester(65) is shown in FIG. 20.

EXAMPLE 22 (cf. Synthetic schemes II and VII) Synthesis of13,14-dihydro-15-keto-16R,S-fluoro-PGF₂ α (68) (22-1) Synthesis of13,14-dihydro-15-keto-16R,S-fluoro-9,11-bis(2-tetrapyranyloxy)-PGF₂ α(67)

Ester (24) (0.796 g) was stirred overnight with lithium hydroxide (0.5mol/100 ml) in THF (50 ml) at room temperature. After acidified withhydrochloric acid in an ice bath, the solution was extracted with ethylacetate. The crude product (66) obtained after concentration underreduced pressure was oxidized with Jones reagent in acetone at -15° C.to give ketone (67). Yield; 0.330 g

(22-2) Synthesis of 13,14-dihydro-15-keto-16R,S-fluoro-PGF₂ α (68)

Ketone (67) (0.330 g) was kept in a mixed solvent (aceticacid/water/THF=4/2/1) (25 ml) at 45° C. for 3 hours. After the usualwork-up, the product was chromatographed (ethyl acetate/hexane=1/3-2/3)to give 13,14-dihydro-15-keto-16R,S-fluoro-PGF₂ α (68) as a pale yellowoil. Yield; 0.112 g

NMR spectrum of 13,14-dihydro-15-keto-16R,S-fluoro-PGF₂ α (68) is shownin FIG. 21. Mass (DI) m/z 372 (M⁺), 354 (M⁺ -18), 336, 284, 256

EXAMPLE 23 (cf. Synthetic scheme VII) Synthesis of13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-PGF₂ α (69) ##STR33##

In the same manner as described in Example 22,13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-PGF₂ α (69) was preparedwith using (-)-Corey lactone (1) and dimethyl(3R,S-fluoro-2-oxononyl)phosphonate obtained according to theconventional method.

NMR spectrum of 13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-PGF₂ α (69)is shown in FIG. 22. Mass (DI) m/z 400 (M⁺), 382 (M⁺ -18), 362, 344

EXAMPLE 24 (cf. Synthetic scheme IV) Synthesis of13,14-dihydro-15-keto-20-ethyl-PGF₂ α (70) ##STR34##

13,14-Dihydro-20-ethyl-15,15-ethylenedioxy PGF₂ α (43) (0.518 g) wasdissolved in a mixed solvent (acetic acid/THF/water=3/1/1) (10 ml) andheld at 60° C. for 2 hours. After the usual work-up, the resulting crudeproduct was chromatographed to give 13,14-dihydro-15-keto-20-ethyl-PGF₂α (70). Yield; 0.202 g

NMR spectrum of 13,14-dihydro-15-keto-20-ethyl-PGF₂ α (70) is shown inFIG. 23. Mass (DI) m/z 364 (M⁺ -18), 346

EXAMPLE 25 (cf. Synthetic scheme VIII) Synthesis of13,14-dihydro-15-keto-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂ αmethyl ester (82) (25-1) Synthesis of1S-2-oxa-3-oxo-6R-(4-m-trifluoromethylphenoxy-3-t-butyldimethylsilyloxy-1-butyl)-7R-hydroxy-cis-bicyclo(3,3,0)octane(75)

In the same manner as described in Example 5, alcohol (75) was obtainedusing unsaturated ketone (71) which was prepared with using (-)-Coreylactone (1) and dimethyl(3-m-trifluoromethylphenoxy-2-oxopropyl)phosphonate obtained accordingto the usual method.

(25-2) Synthesis of13,14-dihydro-15R,S-t-butyldimethylsilyloxy-9,11-bis(2-tetrapyranyl)oxy-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂α methyl ester (79)

13,14-Dihydro-15R,S-t-butyldimethylsilyloxy-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂α methyl ester (78) (0.50 g) obtained from alcohol (75) according to theusual method was converted into the compound (79) in dichloromethane (50ml) using dihydropyran (1.5 ml) and catalytic amount ofp-toluenesulfonic acid.

(25-3) Synthesis of13,14-dihydro-15R,S-hydroxy-9,11-bis(2-tetrapyranyl)oxy-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂α methyl ester (80)

The above compound (79) was converted into the compound (80) usingtetrabutylammonium fluoride in THF (10 ml). Yield; 0.42 g (77%)

(25-4) Synthesis of13,14-dihydro-15-keto-9,11-bis(2-tetrapyranyl)oxy-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂α methyl ester (81)

The compound (80) (0.42 g) was oxidized with Jones reagent in acetone(15 ml) at -35° C. to give ketone (81). Yield; 0.18 g (43%)

(25-5) Synthesis of13,14-dihydro-15-keto-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂ αmethyl ester (82)

The compound (81) (0.18 g) was dissolved in a mixed solvent (aceticacid/THF/water=3/1/1) (15 ml) and kept at 50° C. for 2 hours. The crudeproduct obtained after the usual work-up was chromatographed to give13,14-dihydro-15-keto-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂ αmethyl ester (82). Yield; 0.123 g (93%)

NMR spectrum of13,14-dihydro-15-keto-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂ αmethyl ester is shown in FIG. 24. Mass (DI) m/z 472, 454, 436, 423

EXAMPLE 26 Synthesis of13,14-dihydro-15-keto-16R,S-fluoro-20-methyl-PGF₂ α methyl ester (83)##STR35##

In the same manner as described in Example 5,13,14-dihydro-15-keto-16R,S-fluoro-20-methyl-PGF₂ α methyl ester (83)was obtained with using (-)-Corey lactone (1) and dimethyl(3R,S-fluoro-2-oxooctyl)phosphonate.

NMR spectrum of 13,14-dihydro-15-keto-16R,S-fluoro-20-methyl-PGF₂ αmethyl ester (83) is shown in FIG. 25.

Mass (DI) m/z 400, 382, 364, 362

EXAMPLE 27 (cf. Synthetic scheme IX) Synthesis of13,14-dihydro-15-keto-16,16-difuloro-PGF₂ α methyl ester (96) (27-1)Synthesis of1S-2-oxa-3-oxo-6R-(4,4-difluoro-3-oxo-1-trans-octenyl)-7R-(p-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(84)

(-)-Corey lactone (1) (6.33 g) was oxidized wtih Collins reagent to givealdehyde (2).

Separately, thallium ethoxide (4.26 g) was dissolved in benzene, towhich was added a solution of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (4.64 g) in benzene, and thesolution was stirred for 30 minutes. The crude product obtained afterthe usual work-up was chromatographed (ethyl acetate/hexane=1/2) to givethe compound (84). Yield; 3.88 g (45%)

(27-2) Synthesis of1S-2-oxa-3-oxo-6R-(4,4-difluoro-3R,S-hydroxy-1-octyl)-7R-(p-phenylbenzoyl)oxy-cis-bicyclo(3,3,0)octane(86)

Enone (84) (3.88 g) was hydrogenated in ethyl acetate (40 ml) with using5% palladium/carbon (0.39 g) to give the compound (85).

The above compound was reduced in a mixed solvent (THF:methanol=30/70ml) with using NaBH₄ to give alcohol (86). Yield; 4.02 g

(27-3) Synthesis of1S-2-oxa-3-oxo-6R-(4,4-difluoro-3R,S-t-butyldimethylsilyloxy-1-octyl)-7R-hydroxy-cis-bicyclo(3,3,0)octane (88)

Alcohol (86) (4.02 g ) was converted into the corresponding silylether(87) in DMF with using t-butyldimethylsilyl chloride and imidazole. Theproduct was converted to the compound (88) with potassium carbonate(1.14 g) in methanol (80 ml). Yield; 2.89 g (83%)

(27-4) Synthesis of 13,14-dihydro-15-keto-16,16-difluoro-PGF₂ α methylester (96)

In the same manner as described in Example 5, using the compound (88)(2.89 g), the synthetic intermediate (92) was obtained. Yield; 3.02 g

In the same manner as described in Example 5, using the compound (92)(0.44 g), 13,14-dihydro-15-keto-16,16-difluoro-PGF₂α methyl ester (96)was obtained. Yield; 0.168 g

NMR spectrum of 13,14-dihydro-15-keto-16,16-difluoro-PGF₂ α methyl ester(96) is shown in FIG. 26. Mass (DI) m/z 404, 386, 368, 355

EXAMPLE 28 (CF. SYNTHETIC SCHEME X) Synthesis of13,14-dihydro-15-keto-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂ α(100) (28-1) Synthesis of tetrapyranyl ether (97)

The crude carboxylic acid (77) was converted to the correspondingtetrapyranyl ether (97) in dichloromethane with using excessive amountof dihydropyran and p-toluenesulfonic acid as a catalyst. Yield; 0.63 g

(28-2) Synthesis of alcohol (98)

The above tetrapyranyl ether (97) (0.63 g) was converted to thecorresponding alcohol (98) in THF with using tetrabutylammoniumfluoride. Yield; 0.38 g

(28-3) Synthesis of ketone (99)

The above alcohol (98) (0.38 g) was oxidized with Collins reagent togive ketone (99). Yield; 0.34 g

(28-4) Synthesis of13,14-dihydro-15-keto-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂ α(100)

The above ketone (99) (0.34 g) was kept in a mixed solvent (aceticacid/THF/water=3/1/1) at 45°-50° C. for 4.5 hours. After completion ofthe reaction, the reaction solution was concentrated. The resultingresidue was chromatographed to give13,14-dihydro-15-keto-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂ α(100). Yield; 0.1 g

NMR spectrum of13,14-dihydro-15-keto-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂.alpha.(100) is shown in FIG. 27. Mass (DI) m/z 458, 441, 423

NMR data of the intermediates obtained in the above Examples 6-27 isshown below:

(30)δ: 0.05 (6H, s), 0.88 (9H, s), 0.75-1.05 (3H), 1.05 -2.5 (23H, m),2,42 (3H, s), 3.63 (3H, s), 3.4-4.7 (4H, m), 5.37 (2H, m), 7.28 (2H, d,J=9Hz), 7.75 (2H, d, J=9Hz).

(31) 0.05 (6H, s), 0.88 (9H, s), 0.75-1.05 (3H), 1.05-2.7 (20H, m), 3.63(3H, s), 3.5-3.85 (1H), 3.85-4.1 (0.5H, m), 4.4-4.65 (0.5H, m), 5.35(2H, m), 6.09 (1H, dd, J=6Hz, J=3Hz), 7.53 (1H, dd, J=6Hz, 3Hz).

(39) 0.87 (3H, t, J=6Hz), 1.05-3.0 (22H, m), 4.93-5.25 (2H, m), 2.2-8.1(9H, m).

(41) 0.87 (3H, t, J=6Hz), 1.0-3.0 (23H, m), 3.88 (4H, s), 3.6-4.2 (1H),4.91 (1H, dt, J=6Hz, J=3Hz)

(62) 0.88 (3H, s), 1.05-2.4 (30H, m), 3.60 (3H, s), 3.88 (4H, s),3.2-4.3 (3H, m), 4.6 (1H, bS), 5.11 (1H, m), 5.40 (2H, m), 7.3-8.1 (5H,m).

(63) 0.89 (3H, s), 1.0-2.4 (31H, m), 3.62 (3H, s), 3.87 (4H, s), 3.3-4.2(4H, m), 4.55 (1H, bs), 5.42 (2H, m).

(88) 0.05 (6H, s), 0.87 (9H, s), 0.75-1.0 (3H), 1.05-3.0 (17, m),3.35-3.80 (1H, m), 3.97 (1H, m), 4.88 (1H, dt, J=6Hz, H=3Hz).

(92) 0.08 (6H, s), 0.88 (9H, s), 0.77-1.5 (3H) 1.5-2.5 (29H, m), 3.63(3H, s), 3.3-4.2 (5H, m), 4.62 (1H, m), 5.40 (2H, m).

EXPERIMENT 1

Male Wister rat (8-week old) was anesthetized by intraperitoneallyadministering urethane (1.25 g/kg). Polyethylene tube was inserted intofemoral artery and connected with a pressure transducer to measure bloodpressure.

The test drugs were dissolved in ethanol, diluted with Ringer's solutionbefore use and a dose of 1 mg/kg was administered into tale vein. Themaximum concentration of ethanol was 2%. As reference, ethanol-Ringer'ssolution without containing test drugs was used and the effect waschecked in each experiment without failing. The rate of change in bloodpressure (%) was determined by average of 5 data per group.

The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Test Drug   Change in Blood Pressure (%)                                      ______________________________________                                         1          +12                                                                2          +17                                                                3          +14                                                                4          +27                                                                5          +18                                                                6          +44                                                                7          +26                                                                8          + 7                                                                9          +41                                                               10          +18                                                               11          +20                                                               12          +16                                                               13          + 8                                                               14          +32                                                               15          + 7                                                               16          +14                                                               17          +10                                                               18          +13                                                               19          + 8                                                               20          + 5                                                               21          +16                                                               22          + 7                                                               23          +35                                                               24          +24                                                               25          + 5                                                               26          0                                                                 ______________________________________                                         Test Drugs                                                                    (1) 13,14dihydro-15-keto-PGF.sub.2 α methyl ester                       (2) 13,14dihydro-15-keto-PGF.sub.2 α ethyl ester                        (3) 13,14dihydro-15-keto-9PGF.sub.2 α methyl ester                      (4) 13,14dihydro-15-keto-16,16-dimethyl-PGF.sub.2 α ethyl ester         (5) 13,14dihydro-15-keto-16R,S-fluoro-PGF.sub.2                               (6) 13,14dihydro-15-keto-16R,S-fluoro-PGF.sub.2 α methyl ester          (7) 13,14dihydro-15-keto-16,16-difluoro-PGF.sub.2 α methyl ester        (8) 13,14dihydro-15-keto-16R,S-fluoro-11R-methyl-PGF.sub.2 α methyl     ester                                                                         (9) 13,14dihydro-15-keto-16R,S-fluoro-20-methyl-PGF.sub.2 α methyl      ester                                                                         (10) 13,14dihydro-15-keto-16R,S-fluoro-20-ethyl-PGF.sub.2                     (11) 13,14dihydro-15-keto-16R,S-fluoro-20-ethyl-PGF.sub.2 α methyl      ester                                                                         (12) 13,14dihydro-15-keto-16R,S-fluoro-20-ethyl-11R-methyl-PGF.sub.2          α  methyl ester                                                         (13) 13,14dihydro-15-keto-17S-methyl-PGF.sub.2 α ethyl ester            (14) 13,14dihydro-15-keto-20-methyl-PGF.sub.2 α methyl ester            (15) 13,14dihydro-15-keto-20-methyl-PGF.sub.2                                 (16) 13,14dihydro-15-keto-20-ethyl-PGF.sub.2 α methyl ester             (17) 13,14dihydro-15-keto-20-ethyl-PGF.sub.2 α ethyl ester              (18) 13,14dihydro-15-keto-20-ethyl-PGF.sub.2 α isopropyl ester          (19) 13,14dihydro-15-keto-20-ethyl-PGF.sub.2 α nbutyl ester             (20) 13,14dihydro-15-keto-20-ethyl-PGF.sub.2 α methyl ester             (21) 13,14dihydro-15-keto-20-n-propyl-PGF.sub.2 α methyl ester          (22) 13,14dihydro-15-keto-20-n-butyl-PGF.sub.2 α methyl ester           (23)                                                                          13,14dihydro-15-keto-16-desbutyl-16-(m-trifluoromethylphenoxy)-PGF.sub.2      α methyl ester                                                          (24) 13,14dihydro-15-keto-PGF.sub.1 α ethyl ester                       (25) 13,14dihydro-15-keto-20-ethyl-PGF.sub.1 α methyl ester             (26) Ringer's solution                                                   

As is obvious from the above results,13,14-dihydro-15-keto-prostaglandins of the F series of the presentinvention distinctly show vasopressor effect. Further, it has been foundthat those containing halogen such as fluorine or lower alkyl group suchas methyl or phenoxy especially show surprisingly great vasopressoreffect.

EXPERIMENT 2 Measurement of pulse

Male Wister rate (8-week old) was anesthetized by intraperitoneallyadministering urethane (1.25 g/kg). A tachometer was operated by R waveof electrocardiogram of exterminal derivation. The effect of the tested15-keto-PGEs on pulse is evaluated by the value calculated from thefollowing formula: ##EQU1## The results are shown in Table 2.

EXPERIMENT 3 Trachea contraction

Trachea was enucleated from Std : Hartley guinea pig, longitudinallyincised heterolateral side to trachea unstriated muscle, thentransversely truncated. The resulting ring-shaped trachea tissue (7pieces) were connected like chain with string and suspended in a magnustube into which Krebs buffer containing enzyme was filled. The each testdrug was dissolved in ethanol and then diluted with distilled water,which was applied to Krebs buffer in the magnus tube. The concentrationof ethanol was controlled at less than 0.2%. The contraction by the testdrug was indicated by EC₅₀, which is a concentration of the drug showing50% contraction when the contraction by 30 mM KCl is assumed 100%. Theresults are shown in Table 2.

EXPERIMENT 4 Airway resistance

Male Std : Hartley guinea pig was anesthetized by intraperitoneallyadministering urethane (1.5 g/kg). After cannulation in trachea, 0.3mg/kg of parachronium was intravenously administered to immobilize, andartificial respiration was conducted using a respirator. The change inthe inner pressure of the airway was recorded using bronchospasmtransducer. The test drug was intravenously administered through thepolyethylene tube inserted in the external jugular vein. The drug whichraised the inner resistance of the airway when administered at the doseof 1 mg/kg was evaluated as positive for airway resistance raisingactivity.

The results are shown in Table 2.

EXPERIMENT 5 Enteron contraction

Ileum was removed from male Wister rat and suspended in a magnus tube.Contraction was induced several times with acetylcholine at theconcentration of 1×10⁻⁶ g/ml. After more than two contractions with sameintensity were obtained, the test drug was administered in the samemanner as in Experiment 3. Contraction by the test drug was indicated byEC₅₀, which is a concentration of the test drug showing 50% contraction,when the contraction induced by 1×10⁻⁶ g/ml of acetylcholine is assumed100%.

The results are shown in Table 2.

EXPERIMENT 6 Acute toxicity

Using Male Slc-ddY mouse (5 weeks old), acute toxicity upon oraladministration (LD₅₀) was examined. The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                 Drug 18  Drug 16    Drug 1  PGF.sub.2 α                        ______________________________________                                        Blood Pressure*                                                                          ↑    ↑    ↑                                                                             ↓→↑                Pulse*     →   →   ↑                                                                             ↓→↑                Trachea**  -          -          -     +                                      Contraction                                                                   Airway***  -                           +                                      Resistance                                                                    Enteron**  -          -          -     ++                                     Contraction                                                                   LD.sub.50 (oral)                                                                         > 2000 mg/kg                                                                             > 2000 mg/kg                                            ______________________________________                                         *↑: increase more than 10%                                              ↓: decrease more than 10%                                              →: no change observed                                                  **++: EC.sub.50 < 10.sup.-7                                                   +: 10.sup.-7 ≦ EC.sub.50 ≦                                      -: 10.sup.-6 < EC.sub.50                                                      ***-: no effect                                                               +: increase airway resistance                                            

As is obvious from the above results, 13,14-dihydro-15-keto-PGFs did notshow ephemeral decrease in pulse as well as blood pressure which PGF₂ αusually shows. Further, 13,14-dihydro-15-keto-20-alkyl PGFs are found toshow no effect on pulse. 13,14-Dihydro-15-keto-PGFs show no or extremelyreduced effect on trachea or enteron contraction without showingside-effect such as increase in airway resistance. Therefore,13,14-dihydro-15-keto-PGFs are useful as vasopressor with no or littleside-effects. Particularly, 13,14-dihydro-15-keto-20-alkyl-PGFs are freefrom side effect, i.e., slight increase in pulse and specifically showvasopressor activity. Moreover, their toxicity are extremely weak, thatis, no death was caused by oral administration of 2,000 mg/kg of thecompound. ##STR36##

What is claimed is:
 1. A 13,14-dihydro-15-keto-PGF represented by theformula:in which a bond between C-2 and C-3 is a single or a doublebond, X is a group: ##STR37## R₁ is a hydrogen atom or a C₁₋₄ alkyl,phenyl, benzoyl, hydroxyalkyl, alkoxyalkyl, trialkylsilyl ortetrahydropyranyl group; R₂ is a hydrogen atom or a lower alkyl group;R₃ is hydroxyl; R₃ is hydroxyl; R₄ and R₅ are the same or different, andsignify a hydrogen atom, a halogen atom, or a lower alkyl group; andwhen at least one of R₄ and R₅ is a halogen atom, R₆ is a C₄₋₉ alkylgroup which may be branched or contain a double bond, a C₁₋₉ alkyl groupcontaining a C₁₋₂ alkoxy substituent or ##STR38## (wherein R₇ is ahydrogen or halogen atom or a halogenated methyl group); or when R₄ andR₅ are independently a hydrogen atom or a lower alkyl group, R₆ is aC₆₋₉ alkyl group which may be branched or contain a double bond, a C₁₋₉alkyl group containing a C₁₋₂ alkoxy substituent or ##STR39## (whereinR₇ is as above defined); and a physiologically acceptable salt of said13,14-dihydro-15-keto-PGF.
 2. 13,14-dihydro-15-keto-PGFs according toclaim 1, wherein R₁ is an alkyl group h aving a carbon number of one tofour.
 3. 13,14-dihydro-15-keto-PGFs and physiologically acceptable saltsthereof according to claim 1, wherein at least one of R₄ and R₅ is ahalogen atom.
 4. 13,14-dihydro-15-keto-PGFs and physiologicallyacceptable salts thereof according to claim 1, wherein at least one ofR₄ and R₅ is a lower alkyl group.
 5. 13,14-dihydro-15-keto-PGFs andphysiologically acceptable salts thereof according to claim 1, whereineach of R₄ and R₅ is a lower alkyl group.
 6. 13,14-dihydro-15-keto-PGFsand physiologically acceptable salts thereof according to claim 1,wherein each of R₄ and R₅ is a halogen atom. 7.13,14-dihydro-15-keto-PGFs and physiologically acceptable salts thereofaccording to claim 1, being13,14-dihydro-15-keto-16-desbutyl-16-trifluoromethyl-phenxoy-PGFs. 8.13, 14-dihydro-15-keto-PGFs and physiologically acceptable salts thereofaccording to claim 1 being a 13,14-dihydro-15-keto-16, R,S-fluoro-PGF₂α-methyl ester.
 9. A 13,14-dihydro-15-keto-PGF of claim 1 being a13,14-dihydro-15-keto-20-ethyl-PGF represented by the formula: ##STR40##or a physiologically acceptable salt thereof.
 10. A13,14-dihydro-15-keto-PGF of claim 1 being a13,14-dihydro-15-keto-16-substituted-PGF represented by the formula:##STR41## wherein at least one of R₄ and R₅ is a halogen atom; or aphysiologically acceptable salt thereof.
 11. A 13,14-dihydro-15-keto-PGFof claim 1 being a 13,14-dihydro-15-keto-16-desbutyl-16-phenoxy-PGFrepresented: by the formula: ##STR42## or a physiologically acceptablesalt thereof.
 12. A 13,14-dihydro-15-keto-PGF of claim 1 being a13,14-dihydro-15-keto-20-ethyl-PGF₂α, a C₁ -C₄ alkyl ester or aphysiologically acceptable salt thereof.
 13. A 13,14-dihydro-15-keto-PGFof claim 1 being a 13,14-dihydro-15-keto-20-ethyl-PGF₂α isopropyl ester.